Project Summary Clinical lung cancer therapy is largely limited by how well and for how long treatments remain effective. However, the unfortunate reality is that for many patients with lung cancer their tumors will be resistant to begin with, or quickly acquire resistance, rapidly exhausting the few treatment options available, forcing them into palliative care. Although we have a better understanding of the molecular features of drug-resistant cancer cells, until cancer mortality drops dramatically much more research is needed to understand the molecular origins of resistance, and to develop drugs that can target it. Our goal is to develop therapeutics that are taken before chemotherapy is begun. These treatments will be designed to decrease the resistance of tumors and to extend the effective lifetime of chemotherapy. Our proposal will study the role that specific sphingolipids play in the development of intrinsic drug resistance and transformation. The sphingolipids we are focusing on play important roles cancer but the mechanisms that lead to their alterations have not been studies. Therefore, we are exploring specific mechanisms that might lead to changes in their cellular levels, and whether these changes are active participants in lung epithelial cell transformation and the development of intrinsic drug resistance. A large part of the data presented in this proposal was generated with CURE program K22 Career Development Award.